OTS Rare Disease N-of-1+ Workshop Briefing Document
This briefing document aims to outline the current state of the art of oligonucleotide therapies for those planning to develop individualized therapies for patients with very rare diseases or mutations. The focus is on approved modalities and tissues for which good delivery of oligonucleotides has been confirmed in humans. We believe development of individualized therapies should build on those approaches.
As the oligonucleotide therapy field is dynamic, this document will be dynamic as well. Initially we had planned a meeting to discuss outstanding issues in spring 2020. Currently due to the COVID-19 pandemic, this is not feasible. However, we still believe that a discussion about this topic is timely. We therefore welcome input and comments from the oligonucleotide therapy field in the comment box. This will initiate an online discussion now, and will help us to update this document as needed and also plan for a stakeholder meeting to discuss outstanding issues with those involved (scientists, regulators, patients and funders) in 2021.
Click Here to Read the Briefing Document
Please leave your comments and feedback to the briefing document in the comment box below or email us at raredisease@oligotherapeutics.org.
Thank you for your input, on behalf of the OTS Rare Disease N-of-1+ task force,
Annemieke Aartsma-Rus
Keith Gagnon
Art Krieg
Jon Watts
Tim Yu
This is a very thorough and useful document. I have a few comments:
1) In the Workflow Schematic 1 Step 2 and section 2.3.A consider adding in vivo Pharmacology Studies, especially in established animal models if available.
2) 2.1.A Consent can be obtained from minor’s parent(s), OR legal guardian, OR legally authorized representative to give permission for the minor to take part in the study.
3) 2.3.B re Safety Screening for IT administered drugs I think it is important to note that non-human primates are more likely to translate to human than rodents.
4) 2.4.B re Pharmacokinetic studies – if these are required then it should be noted that development of the correct assays can require substantial effort and resources.
5) 2.4.B Should there be a comment about preference for using juvenile animals to study safety effects if the intended patients are pediatric?
6) 2.4.C Clinical Safety Issues should note the potential for thrombocytopenia – this is a warning that is present on several ASO labels.
7) 2.4.C Clinical Safety – IT ASO can cause transient hindlimb hyporeflexia, paresis or ataxia when administered in cynomolgus monkeys. The relevance of this to humans is uncertain.
8) section 3 – Assuring fair access is a complicated ethical issue. There should be an effort to establish accepted criteria on how to decide which patients to select for development of N-of-1+ treatment. Thanks for the opportunity to comment.
Thank you very much for your comments, Barry!
Please note that we will update the briefing document regularly and we will implement comment 1 and comment 7 during this update. We will also implement comment 6, and specify that this applies to systemic treatment.
For your comments about safety and pharmacokinetic studies in vivo: the challenge of developing ASO therapies for very small groups of patients (often single individuals) with a progressive disease is that each additional test adds time to the development path during which the entire treatment cohort (i.e. this one individual) will likely irreversably lose functions. As such, we propose to keep the preclinical and safety package as limited as possible and build on experience from similar compounds with similar delivery routes (e.g. milasen and nusinersen), and performing a dose escalation in the patient.
The use of juvenile animals (or not) is something we like to discuss with regulators and the field at large.
Comment 8: we fully agree! This is something we want to discuss during the face to face meeting. The current document gives some guidance on who best to select, but this is only the start.
Thanks again for your comments and everyone feel free to comment to the comments or the reply – we hope to get a virtual discussion going while face to face discussions are not possible.
Very thoughtful comments, Barry, Thanks! As Annemieke mentioned, we’ll update the document, trying to highlight the key issues that balance speed and safety so that we also can maximize access. Definitely need to have deeper discussions on all of the issues involved in this with all stakeholders, including bioethicists, patients, and patient advocacy groups.
It’s an exciting time in our field as the technologies that our community has developed are finding so many new opportunities to save lives – how do we safely maximize this? Lot’s more work and discussion needed!